It is remarkable that each one of us carries pathogens such as viruses, bacteria and cancer cells in our bodies, yet we are able to go about our daily lives without worry because our immune system keeps most pathogens in check. So, why does a person become afflicted with cancer or another disease?
The immune system consists of two broadly-defined ‘branches,’ the innate, cellular defense mechanism, defined loosely as Th1, and the adaptive, humoral or antibody-dependent system, defined as Th2. The latter process generates antibodies against antigens derived from digestion of pathogens by phagocytic cells of the innate system. Critical to the development of the Th2 response is activation of the antibody-producing B cells and their differentiation into memory B cells that retain the ability to respond to subsequent challenges from an antigen.
Theoretically, the immune system should be able to mount a response to any type of cancer as well as infectious agents that have unique structures. Activation of immune cells to generate endogenous vaccines, i.e., autovaccination, promotes use of the body's powerful antibody-producing mechanisms against cancer cells and other infective agents. Rather than employing techniques that are effective against specific types, autovaccination should achieve a broad spectrum capacity, i.e., a technology that can be used for multiple types of cancer. However, to achieve this goal, the cell-mediated branch of the immune system must be activated, within which are the antibody-producing memory B cells. Destruction of cancer cells then occurs by antibody-dependent cellular cytotoxicity (ADCC) performed by macrophages, neutrophils and natural killer cells.
Thus in most cases of a person being afflicted with cancer, the person's immune system has been weakened, for example by stress, illness malnutrition, or age. A weakened immune system allows infective agents such as viruses or bacteria that may have been latent for many years to emerge and cause disease, including cancer. In addition, the infective agent or cancer cell may have learned how to evade the immune system's defenses. These pathogens can achieve this “escape” in a number of ways. For cancer cells, they can either suppress the immune system or make themselves look like normal tissues.
Although fighting bacterial infections with “antibiotics” has been relatively easy, because bacteria are easy, non-human targets for drugs that are relatively safe and easy to use. And even when the bacteria become resistant to the “antibiotic,” there are other “antibiotics” available. On the other hand, treating cancers and viral infections has not been easy. Not only do these treatments target human processes, and thus tend to be quite toxic, they are also susceptible to resistance. Therefore, there is a need for treatments that overcome the ability of pathogens, for example cancer cells, to “escape.” In particular, there is a need for drugs that expand, mature, and activate the immune system and, most importantly, do not have the toxic effects are caused by chemotherapy drugs and antibody therapies.
Immunotherapy has had an uneven history with periods of hope followed by periods of disappointment. However, recently new approaches have again opened options for therapy that have caused great enthusiasm, so much so that Science Magazine in December 2013 called cancer immunotherapy “Breakthrough of the Year.” This declaration followed the successful use of monoclonal antibodies against certain cancers, in particular melanoma. In contrast to the polyclonal response of the endogenous immune system, treatment with a monoclonal antibody targets a single antigen. Monoclonal antibodies have been developed to block inflammation and the activity of angiogenic cytokines to reduce blood flow into tumors. The most dramatic antibiotics therapies have been antibodies against inhibitory receptors on T cells such as CTLA-4 and PD-1 Inhibition of the function of these receptors leads to enhanced activity of cytotoxic T cells, which are capable of killing cancer cells. In addition, inhibition of CTLA-4 causes a reduction in inhibitory, regulatory T cells by binding to this receptor, which is expressed at elevated levels in tumors and thereby marks these cells for destruction by macrophages. The use of these antibodies is still accompanied by serious toxic side-effects, which often must be controlled by anti-inflammatory steroids.
Accordingly, there is a need in the art for improved methods for the treatment of diseases and condition where the pathogen “escapes” the immune response (for example cancers), at least in terms of prolonging subject survival and/or quality of life.